Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line

Abstract

BackgroundOsteosarcoma is a bone-forming tumor of mesenchymal origin that presents a clinical pattern that is consistent with the cancer stem cell model. Cells with stem-like properties (CSCs) have been identified in several tumors and hypothesized as the responsible for the relative resistance to therapy and tumor relapses. In this study, we aimed to identify and characterize CSCs populations in a human osteosarcoma cell line and to explore their role in the responsiveness to conventional therapies.MethodsCSCs were isolated from the human MNNG/HOS cell line using the sphere formation assay and characterized in terms of self-renewal, mesenchymal stem cell properties, expression of pluripotency markers and ABC transporters, metabolic activity and tumorigenicity. Cell's sensitivity to conventional chemotherapeutic agents and to irradiation was analyzed and related with cell cycle-induced alterations and apoptosis.ResultsThe isolated CSCs were found to possess self-renewal and multipotential differentiation capabilities, express markers of pluripotent embryonic stem cells Oct4 and Nanog and the ABC transporters P-glycoprotein and BCRP, exhibit low metabolic activity and induce tumors in athymic mice. Compared with parental MNNG/HOS cells, CSCs were relatively more resistant to both chemotherapy and irradiation. None of the treatments have induced significant cell-cycle alterations and apoptosis in CSCs.ConclusionsMNNG/HOS osteosarcoma cells contain a stem-like cell population relatively resistant to conventional chemotherapeutic agents and irradiation. This resistant phenotype appears to be related with some stem features, namely the high expression of the drug efflux transporters P-glycoprotein and BCRP and their quiescent nature, which may provide a biological basis for resistance to therapy and recurrence commonly observed in osteosarcoma.

Cancer stem cells in osteosarcoma

“…This was followed by several other groups, which further showed that sphere forming cells were tumorigenic in immunodeficient mice and that these cells were more drug resistant suggesting a CSC phenotype (36). A detailed study on the sphere forming fraction of MNNG/HOS cells was done by Martins-Neves et al (37) who showed that cells isolated from spheres had mesenchymal stem cell properties including upregulated gene expression of stemness genes Oct3/4, Nanog, and ABC transporters. They went on to show that sphere cells were more resistant to chemotherapy and radiation and that these cells exhibited higher cancer-initiating properties in vivo when compared to parental cells.…”

Transcription factor Oct4 promotes osteosarcoma by regulating lncRNA AK055347

“…Thus, the poor prognosis of osteosarcoma likely results in failure of treatment to target the osteosarcoma stem cells (11). In previous studies investigating the role of Oct4 in osteosarcoma, Oct4 was overexpressed in stem-like cells isolated from the human osteosarcoma MNNG/HOS cell line (12) and promoted tumor formation when OCT4 was exogenously expressed in the human osteosarcoma cell line (11). Overexpression of imprinted tumor-suppressing subtransferable candidate 3, an apoptosis-associated gene, efficiently downregulated the expression of Oct4 as well as homeobox protein NANOG (NANOG) and SRY (sex determining region Y)-box 2 (Sox2), which are two members of the pluripotency transcription factor family, in tumor initiating cells, decreased the clone formation rate, and downregulated tumorigenesis in the MThFOB1.19 osteoblast cell line (13).…”

Doxorubicin activates the Notch signaling pathway in osteosarcoma

“…Various factors contribute to this heterogeneic response, in which cell hierarchy plays an important role. A number of reports have identified the existence of osteosarcoma stem cells, a subpopulation of cells that possess the capacity to self-renew and multi-differentiate (7)(8)(9). In addition, cancer stem cells participate in drug resistance, thus contributing to treatment failure (10,11).…”